Inflammation leading to tissue damage is regulated by numerous phlogistic mediators. Since eosinophils, neutrophils, basophils, lymphocytes and mast cells contain large numbers and amounts of proteases, they appear to be implicated both in the regulation of inflammation and in the damage incurred during inflammation. Essentially any connective tissue can be degraded by one or more proteases.
Human neutrophils utilize a variety of destructive enzymes during the process of phagocytosis. The major enzymes have been determined to be elastase, cathepsin G, myeloperoxidase and lysozyme.
It has now been found that controlling the amount of the destructive enzymes at the site of inflammation can prevent proliferation of the disease, prevent associated tissue damage and promote healing. It has also been found that the administration of alpha 1-antitrypsin alone provides a major control of the symptoms of the disease or burns. However, since the cause of disease may be a result of more than one factors, the use of more than one protease inhibitor provides a better chance of success for early remission of the symptoms and for a prophylactic control of the symptoms associated with the disease. Alpha 1-antitrypsin when administered with other serine protease inhibitors, for example, alpha 2-macroglobulin, alpha 1-antichymotrypsin and C-reactive protein (CRP), provides a reduction in swelling, pain and stiffness.
Alpha 1-antichymotrypsin is a plasma protease inhibitor synthesized in the liver. It is a single glycopeptide chain of approximately 68,000 daltons and belongs to a class of serine protease inhibitors with an apparent affinity toward chymotrypsin-like enzymes. Alpha 1-antichymotrypsin is structurally related to alpha 1-antitrypsin.
Alpha 2-macroglobulin is a glycoprotein containing 8-11% carbohydrate which can be isolated from plasma by gel filtration chromatography.
Alpha 1-proteinase inhibitor (alpha 1-antitrypsin) is a glycoprotein having a molecular weight of 53,000 determined by sedimentation equilibrium centrifugation. The glycoprotein consists of a single polypeptide chain to which several oligosaccharide units are covalently bonded. Human alpha 1-proteinase inhibitor has a role in controlling tissue destruction by endogenous serine proteinases. A genetic deficiency of alpha-1-proteinase inhibitor, which accounts for 90% of the trypsin inhibitory capacity in blood plasma, has been shown to be associated with the premature development of pulmonary emphysema. The degradation of elastin associated with emphysema probably results from a local imbalance of elastolytic enzymes and the naturally occurring tissue and plasma proteinase inhibitors. Alpha-1-proteinase inhibitor inhibits human pancreatic and leukocyte elastases. See Pannell et al, Biochemistry. 13, 5339 (1974); Johnson et al, Biochem. Biophys. Res. Commun., 72 33 (1976); Del Mar et al, Biochem. Biophys. Res. Commun., 88, 346 (1979); and Heimburger et al, Proc. Int. Res. Conf. Proteinase Inhibitors. 1st, 1-21 (1970).
U.S. Pat. No. 4,916,117 to Lezdey et al discloses the treatment of pulmonary inflammation with microcrystalline alpha-1-antichymotrypsin.
U.S. Pat. No. 4,732,973 to Barr et al, which is herein incorporated by reference, discloses the preparation of the analogs of human-1-antitrypsin wherein the amino acid corresponding to the methionine at position 358 of wild-types alpha-1-antitrypsin is substituted with an aliphatic amino acid.